An intensive effort was directed toward attempting to better understand the immunopathologic mechanisms underlying the immunodeficiency of HIV-1 infection. To determine whether or not alterations in the fine specificity of the CD4+ T lymphocyte repertoire could underly the defect, a polymerase chain reaction (PCR) based technique was used to determine the relative levels of mRNAs encoding the T cell antigen receptor beta- chain for each of the 24 human variable domain beta-chain subfamilies. Disruptions of the normal size pattern were noted in the majority of patients with HIV infection, particularly those patients with low CD4+ T lymphocyte counts. While protease or IL-2 therapy could result in substantial increases in CD4+ T lymphocyte numbers, they led to little if any changes in the distribution of size patterns. The HIV-hu/PBL-SCID model was employed to study the immune systems of long-term non-progressors and to evaluate the potential anti-viral activity of novel therapeutic interventions. Mice reconstituted with PBMC from long-term non-progressors failed to show evidence of CD4+ T lymphocyte depletion. The nucleoside analogue FddA was found to be a potent anti-retroviral compound. CD8+ T lymphocytes from patients with HIV infection were found to have increased expression of the activiation markers HLA-DR, CD57, CD45RO and Fas. These cells were unable to be stimulated by standard signals. Analysis of these cells revealed increased levels of cdk2 and cyclin E as well as persistence of p27kip, suggesting that they were blocked at the G1/S checkpoint of the cell cycle. A similar phenotype could be generated in vitro by stimulation of CD8+ T lymphocytes from healthy donors with PHA only in the absence of IL-2 suggesting that this in vivo observation may stem from in vivo activation of CD8+ T lymphocytes in the absence of the second signals provided by CD4+ T lymphocytes. Analysis of the T cell receptor repertoire in the CD8+ T lymphocytes of patients with HIV infection revealed that while the DR- subpopulation represented a polyclonal population, the DR+ subpopulation of cells was oligoclonal.